Antiangiogenic Eye Gene Therapy

Abstract

The idea of treating disease in humans with genetic material was conceived over two decades ago and with that a promising journey involving development and efficacy studies in cells and animals of a large number of novel therapeutic reagents unfolded. In the footsteps of this process, successful gene therapy treatment of genetic conditions in humans has shown clear signs of efficacy. Notably, significant advancements using gene supplementation and silencing strategies have been made in the field of ocular gene therapy, thereby pinpointing ocular gene therapy as one of the compelling "actors" bringing gene therapy to the clinic. Most of all, this success has been facilitated because of (1) the fact that the eye is an effortlessly accessible, exceedingly compartmentalized, and immune-privileged organ offering a unique advantage as a gene therapy target, and (2) significant progress toward efficient, sustained transduction of cells within the retina having been achieved using nonintegrating vectors based on recombinant adeno-associated virus and nonintegrating lentivirus vectors. The results from in vivo experiments and trials suggest that treatment of inherited retinal dystrophies, ocular angiogenesis, and inflammation with gene therapy can be both safe and effective. Here, the progress of ocular gene therapy is examined with special emphasis on the potential use of RNAi- and protein-based antiangiogenic gene therapy to treat exudative age-related macular degeneration.

In Vivo Knockout of the Vegfa Gene by Lentiviral Delivery of CRISPR/Cas9 in Mouse Retinal Pigment Epithelium Cells

“…In this study, we demonstrate for the first time in vivo gene knockout in the murine retina mediated by LVs encoding sgRNA and SpCas9 targeted to the Vegfa gene in the retinal pigment epithelium (RPE) cells. As dysregulation of the Vegfa gene, which promotes aberrant angiogenesis, is linked to exudative AMD 22 , 23 , 24 as well as other retinal neovascular disorders, the presented data further support the notion that in vivo genome knockout with Cas9 may provide a new platform for the treatment of AMD.…”

The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

“…Specifically targeting HIF transcription factors have been an attractive strategy for the treatment of the multifactorial nAMD [226][227][228]. Currently, only animal models of CNVassociated with nAMD have been addressed with anti-HIF gene therapies.…”

c-Jun-mediated microRNA-302d-3p induces RPE dedifferentiation by targeting p21Waf1/Cip1

“…Compared to traditional therapeutic strategies, miRNA-based treatments have more advantages in drug efficiency and delivery 16 . Gene therapies targeting miRNAs in treating CNV have also been well developed 43 , 44 . Therefore, miR-302d-3p inhibitors with high efficiency, including tough decoys (TuDs) and small guide RNA with CRISPR/Cas9 system, are prospective in suspending or even preventing AMD disease course 45 , 46 .…”